Stable emulsions and dry powders of mixtures of fat-soluble vitamins, their preparations and use

ABSTRACT

The present invention relates to stable emulsions and dry powders of mixtures of fat-soluble vitamins, and to processes for their preparation and to their use.

This application is a division of application Ser. No. 08/948,061 filedOct. 9, 1997.

The present invention relates to novel stable emulsions and dry powdersof mixtures of fat-soluble vitamins, and to a process for theirpreparation and to their use.

Fat-soluble vitamins play an important part in human and animalnutrition. It is common to these fat-soluble agents that, in their pureform, they can be handled only with difficulty or not at all becausethey are oxidation-sensitive substances. Furthermore, a fine dispersionof the agent is advantageous for optimal absorbability and thusbioavailability. These substances are therefore often supplied in theform of emulsions or, preferably, in the form of dry powders, where theagents, either in pure form or as solution in a physiologicallytolerated oil, are embedded in a fine dispersion in a protectivecolloid.

Dry powders of fat-soluble vitamins can be prepared on the basis offormulation processes disclosed in the literature, describedcomprehensively inter alia in R. A. Morton, Fat Soluble Vitamins,Intern. Encyclopedia of Food and Nutrition, Volume 9, Pergamon Press1970, pages 134-139. These entail the fat-soluble vitamin beingemulsified into an aqueous protective colloid solution, homogenized andsubsequently dried, where appropriate in the presence of a coatingmaterial.

The protective colloids frequently used are the biopolymers described inthe patents DE-A-1 123 084, U.S. Pat. Nos. 2,756,177, 4,670,247 and inEP-A-0 285 682, EP-A-0 565 989 and DE-A-44 24 085, such as gelatin, gumarabic, starch, lignin or else partially hydrolyzed soya protein, andother substances obtained from natural sources. A compilation ofcommercial protective colloids is likewise to be found in R. A. Morton,Fat Soluble Vitamins, Intern. Encyclopedia of Food and Nutrition, Volume9, Pergamon Press 1970, pages 130/131.

When dry powders which comprise mixtures of fat-soluble vitamins whosecomposition is adapted to physiological requirements and in which theindividual components are in some cases present in extremely large orsmall amounts relatively are used, the requirements to be met by theformulating are particularly stringent. In this case, it is particularlyimportant for the user that, besides the required stability, ahomogeneous equal dispersion of the agents in all the particles isensured.

It is an object of the present invention to propose a process forpreparing stable mixtures of fat-soluble vitamins in finely dispersedform. It was furthermore the intention to provide dry powders offat-soluble vitamins in which, besides the required stability, ahomogeneous equal dispersion of the agents in all the particles isensured.

The term “fat-soluble vitamins” comprises for the purpose of the presentinvention in particular vitamins A, D, E and/or K, the correspondingprovitamins and vitamin derivatives such as esters with an actionresembling that of vitamin A, D, E or K, and the term “vitamin(A,D,E,K)” formulated in the claims likewise comprises their derivativesand a mixture thereof.

We have found that this object is achieved by a process for preparing astable emulsion or a stable dry powder of fat-soluble vitamins whichcomprises emulsifying in each case separately in water:

a) vitamin K and

b) a mixture of vitamin D, vitamin E and vitamin A or an inert oil or amixture of vitamin A and an inert oil, obtainable by

b₁) dissolving vitamin D in an inert oil and/or vitamin A, and mixingwith vitamin E, or

b₂) adding vitamin D to a mixture of vitamin E and vitamin A and/or aninert oil,

carrying out the emulsification of components a) and b) in each case inthe presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate other additives,

subsequently mixing the emulsions and drying the mixture to prepare astable vitamin dry powder, where appropriate in the presence of acoating material.

If the vitamin mixture is formulated by the processes disclosed in theliterature, in which first the fat-soluble vitamins are mixed and thenemulsified into an aqueous protective colloid solution, homogenized andfinally dried, the following phenomena are to be observed:

An oily mixture, prepared before the emulsification step, of vitamin Kwith vitamin A and/or vitamin E spontaneously becomes deep red. This redcoloration is usually unwanted from the viewpoint of use.

It is furthermore found that a mixture of vitamin E and vitamin D inwhich vitamin E comprises more than 70% by weight results in extensivebreakdown of vitamin D. Thus, for example, the loss of vitamin Dactivity measured in a mixture of 99.6 parts by weight of vitamin E and0.4 part by weight of vitamin D is about 50%.

It is now possible with the aid of the process according to theinvention to eliminate the stability problems and control the color ofthe dry powder as required. Thus, the intrinsic color of the vitamins isretained on separate emulsification of vitamin K on the one hand and themixture of vitamin A, D and/or E on the other hand. Even on subsequentmixing of the two prepared emulsions there is retention of their paleyellow coloration.

It has been possible according to the invention to prevent thesurprising losses of vitamin D activity in the presence of large amountsof vitamin E by first dissolving vitamin D in vitamin A and/or an inertoil, subsequently adding vitamin E to the resulting solution with theparts by weight of vitamin A and/or the inert oil being at least 25%,preferably greater than 50%, especially more than 100%, of the parts byweight of vitamin E. In another variant of the process for stabilizingvitamin D, the concentration of vitamin E is first reduced by “dilution”with at least 25% by weight, preferably more than 50% by weight, ofvitamin A and/or an inert oil, and subsequently vitamin D is added tothis mixture.

For certain applications, eg. for coloring human foods or drugs, astable formulation of the abovementioned red vitamin mixture isadvantageous. A product of this type is obtained by a process accordingto the invention which comprises emulsifying a mixture of

a) vitamin D, vitamin E and vitamin K, and vitamin A or an inert oil ora mixture of vitamin A and an inert oil, obtainable by

a₁) dissolving vitamin D in an inert oil and/or vitamin A, and mixingwith vitamin E and vitamin K, or

a₂) adding vitamin D to a mixture of vitamin E and vitamin K, andvitamin A and/or an inert oil, in the presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate of other additives,

in water and drying the emulsion to prepare a stable vitamin dry powder,where appropriate in the presence of a coating material.

Whereas this variant of the preparation also ensures, by process stepa₁) or a₂), the stability of vitamin D, the mixing of vitamin E withvitamin K before the emulsification produces a dark red oil whose colorcharacterizes the later emulsion and the dry powder obtained afterdrying.

The mixture of fat-soluble vitamins employed in both variants of theprocess according to the invention is composed of 5-90% by weight ofvitamin A and/or an inert oil, 5-90% by weight of vitamin E, 0.01-1% byweight of vitamin D and 0.1-10% by weight of vitamin K, where the % byweight data for the individual components add up to 100%.

A particular embodiment of the abovementioned process is one when thevitamin mixture contains 25-70% by weight of vitamin A and/or an inertoil, 30-70% by weight of vitamin E, 0.05-0.4% by weight of vitamin D and2-8% by weight of vitamin K, where the % by weight data for theindividual components add up to 100%.

Since the two abovementioned processes according to the invention resultin stable emulsions and dry powders of mixtures of the fat-solublevitamins A, D, E and K and of vitamins D, E and K, the aim was also tofind solutions for the stability problems with the following ternarycombinations, namely of vitamins A, D, K; of vitamins A, E, K and ofvitamins A, D, E.

This object has been achieved by the following processes for preparingstable vitamin emulsions and dry powders, which comprise

1) for the vitamin A, D and K ternary combination emulsifying in eachcase separately in water:

a) vitamin K and

b) a mixture of vitamin D and vitamin A,

carrying out the emulsification of components a) and b) in each case inthe presence

c) of one or more protective colloids,

d) where appropriate of ore or more sugars and/or sugar alcohols and

e) where appropriate of other additives,

subsequently mixing the emulsions and drying the mixture to prepare astable vitamin dry powder, where appropriate in the presence of acoating material.

2) for the vitamin A, D and K ternary combination emulsifying:

a) a mixture of vitamin A, vitamin K and vitamin D in the presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate of other additives in water,

and drying the emulsion to prepare a stable vitamin dry powder, whereappropriate in the presence of a coating material.

3) for the vitamin A, E and K ternary combination emulsifying in eachcase separately in water;

a) vitamin K and

b) a mixture of vitamin A and vitamin E,

carrying out the emulsification of components a) and b) in each case inthe presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate of other additives,

subsequently mixing the emulsions, and drying the mixture to prepare astable vitamin dry powder, where appropriate in the presence of acoating material.

4) for the vitamin A, E and K ternary combination emulsifying:

a) a mixture of vitamin A, vitamin E and vitamin K in the presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate of other additives,

in water and drying the emulsion to prepare a stable vitamin dry powder,where appropriate in the presence of a coating material.

5) for the vitamin A, D and E ternary combination emulsifying a mixtureof

a) vitamin D, vitamin E and vitamin A or an inert oil or a mixture ofvitamin A and an inert oil, obtainable by

a₁) dissolving vitamin D in an inert oil and/or vitamin A, and mixingwith vitamin E, or

a₂) adding vitamin D to a mixture of vitamin E and vitamin A and/or aninert oil,

in the presence

c) of one or more protective colloids,

d) where appropriate of one or more sugars and/or sugar alcohols and

e) where appropriate other additives,

in water, and drying the emulsion to prepare a stable vitamin drypowder, where appropriate in the presence of a coating material.

The mixture of fat-soluble vitamins employed in processes 1) and 2)according to the invention is composed of 70-98% by weight of vitamin A,0.01-1% by weight of vitamin D and 2-30% by weight of vitamin K.

The mixtures of fat-soluble vitamins employed in processes 3) and 4)have the following composition: 5-90% by weight of vitamin A, 5-90% byweight of vitamin E and 0.1-10% by weight of vitamin K.

The vitamin mixture employed in process 5) according to the invention iscomposed of 5-90% by weight of vitamin A and/or an inert oil, 5-90% byweight of vitamin 2 and 0.01-1% by weight of vitamin D, where the % byweight data for each of the abovementioned individual components add upto 100%.

All five of the variants of the process detailed above for preparingemulsions and dry powders of fat-soluble vitamins which, by definition,comprise a ternary combination from the group of vitamins A, D, E and Kresult in stable products whose color can be adjusted as required by theparticular emulsification process according to the invention.

When carrying out the processes according to the invention, thefat-soluble vitamins are mixed in the first process step, with, in thecase of he vitamin combinations A, D, E, K; D, E, K; A, D, E and D andE, first a solution of vitamin D in vitamin A and/or an inert oil beingprepared at elevated temperature, eg. at from about 40° C. to 80° C.,preferably 50° C. to 70° C. The remaining vitamins are then added tothis solution, and it is emulsified into an aqueous protective colloidsolution at 50° C. to 70° C.

However, it is also possible first to mix vitamin E with vitamin A,vitamin K and/or an inert oil at the abovementioned temperatures inorder thus to reduce the concentration of vitamin E and only then to addvitamin D to this mixture and subsequently emulsify it into an aqueousprotective colloid solution.

In the cases where a red coloration of the vitamin emulsion is unwantedwhen vitamin K is present, it is advantageous to emulsify both vitamin Kand the mixture of vitamins A, E and/or D and, where appropriate, aninert oil in each case separately under the abovementioned conditionsand subsequently to mix these emulsions.

After homogenization and adjustment of the viscosity of the emulsion(s)to 50 to 300 cP, preferably 70 to 150 cP, by appropriate dilution withwater, the emulsion(s) can be converted into a powder product in aconventional way, eg. by spray drying or by spray cooling or by sprayingthe emulsion in a spray tower also using an inert coating material,collecting the coated particles and drying in a fluidized bed.

The stable vitamin dry powders prepared by the process according to theinvention contain 3-40% by weight of a mixture of vitamin A, vitamin D,vitamin E and/or vitamin K and/or an inert oil, 5-40% by weight of aprotective colloid, 0-30% by weight of a sugar and/or sugar alcohol,0-70% by weight of a coating material and, where appropriate, 0-25% byweight of other additives, where the % by weight data for the individualcomponents add up to 100%.

The term “inert oil” means physiologically acceptable oils such assesame oil, corn oil, cottonseed oil, coconut oil, soybean oil or peanutoil, and esters of medium chain-length vegetable fatty acids.

Examples of protective colloids which are used are gelatin, fishgelatin, starch, dextrin, vegetable proteins, pectin, gum arabic,casein, caseinate or mixtures thereof, preferably employing gelatin, gumarabic, vegetable proteins and/or modified starch. However, polyvinylalcohol, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose,hydroxypropylcellulose and alginates are also conceivable as preferableprotective colloids. For further details, reference is made to R. A.Morton, Fat Soluble Vitamins, Intern. Encyclopedia of Food andNutrition, Volume 9, Pergamon Press 1970, pages 128-131. To increase themechanical stability of the final product, it is expedient to add aplasticizer to a colloid, such as sugars or sugar alcohols, eg. sucrose,glucose, fructose, lactose, invert sugar, sorbitol, mannitol,maltodextrin or glycerol. In preferred embodiments of the processaccording to the invention, sucrose, lactose and/or maltodextrin areemployed.

Other additives which can be added to increase the stability of theagents to oxidative degradation are stabilisers such ast-butylhydroxytoluene, t-butylhydroxyanisole, ascorbic acid orethoxyquin. They are preferably emulsified together with the vitaminsand, where appropriate, additional emulsifiers into the aqueousprotective colloid solution. Examples of emulsifiers which can be usedare ascorbyl palmitate, polyglycerol fatty acid esters, sorbitan fattyacid esters, propylene glycol fatty acid esters or lecithin.

The term coating material means compounds such as starch and/or starchderivatives, and silica and/or silica derivatives, with whose aid thevitamin dry powders are physically stabilized. Preferred coatingmaterials in the human food sector are starch or starch derivatives,especially corn or rice starch.

The products according to the invention can be used both as additives tohuman foods and drugs and for livestock nutrition. In certain cases, itnay also be expedient to use the prepared emulsions directly as such,without converting them into dry powders.

The following examples explain the processes according to the inventionin detail.

EXAMPLE 1

a) Preparation of the Vitamin Mixture

1.7 g (40 million IU/g) oil vitamin D₃ were dissolved by stirring at 65°C. in 500 g (1.7 million IU/g) of preheated vitamin A palmitate, andsubsequently 500 g (1,100 IU/g) of d,1-α-tocopherol and 45 g of vitaminK₁ were added at 65° C.

b) Preparation of the Emulsion

2 kg of gum arabic and 2 kg of sucrose were dissolved in 9 kg ofdistilled water at 65° C. in an emulsifying container. After stirringfor 30 minutes, the vitamin mixture was added and the mixture washomogenized for a further 2 h. Subsequently, the emulsion was dilutedwith water until the viscosity was about 100 cP, and was enveloped instarch and dried in a spray tower.

A yellowish brown vitamin dry powder with the following vitamin contentwas obtained:

Vitamin A palmitate: 91,000 IU/g Vitamin D₃:   7090 IU/g Vitamin K₁:0.41% d,1-α-tocopherol: 4.88%

EXAMPLE 2

a) Preparation of the Vitamin Mixture

1.7 g (40 million IU/g) of vitamin D₃ were dissolved at 65° C. bystirring in 500 g (1,100 IU/g) d,1-α-tocopherol, and subsequently 500 g(1.7 million IU/g) of vitamin A palmitate were added at 65° C.

b) Preparation of the Emulsion

2 kg of gum arabic and 2 kg of sucrose were dissolved in 9 kg ofdistilled water at 65° C. in an emulsifying container. After stirringfor 30 minutes, 500 g of the solution were transferred into a 1 lreactor and homogenized with 45 g of vitamin K₁. The remainingprotective colloid solution was mixed with the vitamin mixture from a)and homogenized for about 2 h. The two emulsions were slowly mixed in aseparate emulsifying container, diluted with water to a viscosity ofabout 100 cP, and enveloped in starch and dried in a spray tower.

A pale yellow vitamin dry powder with the following vitamin content wasobtained:

Vitamin A palmitate: 72,000 IU/g Vitamin D₃:   3340 IU/g Vitamin K₁:0.44% d,1-α-tocopherol: 4.17%

The content of vitamin D₃ fell to about 50% of the amount originallyemployed.

EXAMPLE 3

a) Preparation of the Vitamin Mixture

1.7 g (40 million IU/g) of vitamin D₃ were dissolved by stirring in 500g (1.7 million IU/g) of vitamin A palmitate at 65° C. and subsequently500 g (1,100 IU/g) of d,1-α-tocopherol were added.

b) Preparation of the Emulsion

2 kg of gum arabic and 2 kg of sucrose were dissolved in 9 kg ofdistilled water at 65° C. in an emulsifying container. After stirringfor 30 minutes, 500 g of the solution were transferred into a 1 lreactor and homogenized with 45 g of vitamin K₁. The remainingprotective colloid solution was mixed with the vitamin mixture from a)and homogenized for about 2 h. The two emulsions were slowly mixed in aseparate emulsifying container, diluted with water to a viscosity ofabout 100 cP, and enveloped in starch and dried in a spray tower.

The pale yellow vitamin dry powder had the following vitamin content:

Vitamin A palmitate: 103,000 IU/g Vitamin D₃:   7540 IU/g Vitamin K₁:0.49% d,1-α-tocopherol: 4.68%

EXAMPLE 4

a) Preparation of the Vitamin Mixture:

1.7 g (40 milli on IU/g) of vitamin D₃ were dissolved by stirring in 65g of fractionated coconut oil, and subsequently a mixture, at 65° C., of500 g (1.7 million IU/g) of vitamin A palmitate and 500 g (1,100 IU/g)of d,1-α-tocopherol was added.

b) Preparation of the Emulsion

2 kg of gum arabic and 2 kg of sucrose were dissolved in 9 kg ofdistilled water at 65° C. in an emulsifying container. After stirringfor 30 minutes, 500 g of the solution were transferred into a 1 lreactor and homogenized with 45 g of vitamin K₁. The remainingprotective colloid solution was mixed with the vitamin mixture from a)and homogenized for about 2 h. The two emulsions were slowly mixed in aseparate emulsifying container, diluted with water to a viscosity ofabout 100 cP, and enveloped in starch and dried in a spray tower.

The pale yellow vitamin dry powder had the following vitamin content:

Vitamin A palmitate: 71,600 IU/g Vitamin D₃:   5850 IU/g Vitamin K₁:0.36% d,1-α-tocopherol: 3.96%

EXAMPLE 5

a) Preparation of the Vitamin Mixture

1.2 g (40 million IU/g) of vitamin D₃ were dissolved by stirring in 350g (1.7 million IU/g) of vitamin A palmitate at 65° C., and subsequently350 g (1,100 IU/g) of d,1-α-tocopherol were added.

b) Preparation of the Emulsion

1.4 kg of starch modified with sodium octenyl succinate and 1.4 kg ofsucrose were dissolved in 6.3 kg of distilled water at 65° C. in anemulsifying container. After stirring for 30 minutes, 500 g of thesolution were transferred into a 1 l reactor and homogenized with 33 gof vitamin K₁. The remaining protective colloid solution was mixed withthe vitamin mixture from a) and homogenized for about 2 h. The twoemulsions were slowly mixed in a separate emulsifying container, dilutedwith water to a viscosity of about 100 cP and then enveloped in starchand dried in a spray tower.

The pale yellow vitamin dry powder had the following vitamin content:

Vitamin A palmitate: 85,300 IU/g Vitamin D₃:   7080 IU/g Vitamin K₁:0.44% d,1-α-tocopherol: 4.78%

EXAMPLE 6

a) Preparation of the Vitamin Mixture

2.6 g (40 million IU/g) of vitamin D₃ were dissolved by stirring at 65°C. in 750 g (1.7 million IU/g) of preheated vitamin A palmitate, andthen 750 g (1,100 IU/g) of d,1-α-tocopherol were added at 65° C.

b) Preparation of the Emulsion

2 kg of sodium caseinate and 4 kg of sucrose were dissolved In 7 kg ofdistilled water at 65° C. in an emulsifying container. After stirringfor 30 minutes, 500 g of the solution were transferred into a 1 lreactor and homogenized with 68 g of vitamin K₁. The remainingprotective colloid solution was mixed with the vitamin mixture from a)and homogenized for about 2 h. The two emulsions were slowly mixed in aseparate emulsifying container, diluted with water to a viscosity ofabout 100 cP, and enveloped in starch and dried in a spray tower.

The pale yellow vitamin dry powder had the following vitamin content:

Vitamin A palmitate: 86,500 IU/g Vitamin D₃:   6950 IU/g Vitamin K₁:0.47% d,1-α-tocopherol:  4.8%

EXAMPLE 7

Preparation of the Vitamin Mixture

1.7 g (40 million IU/g) of vitamin D₃ were dissolved by stirring at 65°C. in 500 g (1,100 IU/g) of d,1-α-tocopherol, and then 500 g (1.7million IU/g) of vitamin A palmitate at 65° C. were added. The mixturewas subsequently cooled to 4° C. and stored at this temperature for 2weeks. After 4 and 10 days, the contents of vitamins in the mixture weredetermined.

4 days:

calculated measured Vitamin A palmitate: 850,000 IU/g 848,000 IU/gVitamin D₃:  66,000 IU/g  33,500 IU/g d,1-α-tocopherol: 49.9% 50.0%

10 days:

calculated measured Vitamin D₃: 66,000 IU/g 33,500 IU/g

EXAMPLE 8

The amounts of vitamin D₃ (40 million IU/g) listed in Table 1 or asolution of vitamin D₃ in fractionated coconut oil were mixed withvarious amounts of d,1-α-tocopherol (1,100 IU/g) by stirring at 65° C. Asample of the mixture was analyzed for its vitamin D content immediatelyafter Preparation. One half of the remaining vitamin mixture was in eachcase stored at 65° C. for 24 hours and the second half was stored at 5°C. for 24 hours. The two halves were subsequently investigated for theirvitamin D₃ content.

TABLE 1 Vit. D content Vit. D content Vit. D content Vitamin D Coconutoil Vitamin E (5 min, 65° C.) (24 h, 65° C.) (24 h, 5° C.) Experiment[mg] [g] [g] [% of th.] [% of th.] [% of th.] 1 52.9 14.90 69  2 61 252.3  3.68 10.90 89 50 90 3 51.1  7.28  7.30 93 87 93 4 54.9 10.99  3.6894 86 90

We claim:
 1. A process for preparing a dry powder composition containingvitamins D, E and K or vitamins A, D, E and K, said process comprising:a) homogenizing vitamin K in an aqueous solution containing one or moreprotective colloids for a time and under conditions effective to producean emulsion containing vitamin K, wherein said aqueous solutionoptionally contains one or more sugars or other additives, and whereinsaid emulsion does not contain any of vitamins A, D or E; b)homogenizing in an aqueous solution for a time and under conditionseffective to produce an emulsion, a mixture selected from the groupconsisting of M1, M2 and M3 wherein M1 comprises a protective colloidand vitamins D, E, and A; wherein M2 comprises a protective colloid,vitamin D, vitamin E, and an inert oil; wherein M3 comprises aprotective colloid, an inert oil and vitamins D, E, and A; c) combiningthe emulsions from step a) and b); d) drying the mixture of step c),optionally in the presence of a coating material, to yield a dry powder;and e) isolating the dry powder of step d.
 2. A process as claimed inclaim 1, wherein the dry powder composition contains 5-90% by weight ofvitamin A and/or an inert oil, 5-90% by weight of vitamin E, 0.01-1% byweight of vitamin D, and 0.1% -10% by weight of vitamin K, where the %by weight data for the individual components add up to 100%.
 3. Aprocess as claimed in claim 1, wherein the dry powder compositioncontains 25-70% by weight of vitamin A and/or an inert oil, 30-70% byweight of vitamin E, 0.05-0.4% by weight of vitamin D, and 2-8% byweight of vitamin K, where the % by weight data for the individualcomponents add up to 100%.
 4. A process as claimed in claim 1, whereingelatin, gum arabic, vegetable proteins and/or modified starch is usedas protective colloid, sucrose, lactose and/or maltodextrin is used assugar, and corn starch and/or rice starch is used as coating material.